PROJECT SUMMARY Plasmodium infections and the disease malaria remain global health emergencies. Malaria affected more than 200 million people last year, killing nearly 600,000. Antibody responses that target the parasite are essential for controlling parasite replication and limiting the severity of malaria. Potent antibody responses and optimally stimulated B cells require `help' from CD4+ T cells. Our published work has shown that CD4+ T cell function is markedly impaired following Plasmodium infection. We linked the reduced function of CD4+ T cells to the induction of co-inhibitory receptor expression, a class of T cell surface expressed proteins that directly limit the ability of CD4+ T cells to orchestrate protective immune responses against microbial pathogens. We further showed that blocking the activity of co-inhibitory receptors during malaria restored CD4+ T cell function, promoted strong antibody responses and accelerated parasite control and clearance from the infected host. Recently, we identified that we can also restore the function of Plasmodium-specific CD4+ T cells by activating OX40, a member of a class of T cell stimulating receptors. Our new data show that therapeutically stimulating the OX40 receptor during the second week of experimental Plasmodium infection overcomes co- inhibitory networks, markedly improves CD4+ T cell activity and secreted antibody responses, and limits malaria parasite replication. Importantly, we also identified parallels in children infected with P. falciparum, establishing the relevance and significance of our discoveries and strengthening the scientific premise of the current proposal. In this project we apply new cellular, genetic and parasitological reagents to study how the OX40 receptor regulates communication between parasite specific CD4+ T cells and B cells and the generation of antibody responses. Our scientific questions and experimental approaches facilitate our long- term goal to identify new immune-based approaches to therapeutically stimulate host resistance against malaria. Our goal is addressed by three specific aims that will determine: 1) the distinct characteristics of Plasmodium infection that uniquely regulate the functional expression of OX40 receptors on CD4+ T cells; 2) whether the OX40 receptor is required for effective communication between CD4+ T cells and B cells to generate potent antibody responses; and 3) whether B cell expression of the OX40 ligand is regulated by parasite byproducts and necessary for generating potent secreted antibody responses. Our proposed studies and new reagents provide tractable systems and a detailed framework for sustainable extensions of this project that will establish additional new paradigms for enhancing CD4+ T cell-mediated immunity against Plasmodium. Insight gained during the course of our studies will help us identify and develop new immune- based strategies to limit Plasmodium disease burden.